Ageing is a multifactorial process that affects different layers of the anatomy leading to, at the deepest level, bone resorption and remodelling, resulting in overlying fat redistribution compounded by fat loss, muscle atrophy and, at skin level, dermal ageing through collagen loss. Collagen synthesis stimulants are, therefore, very attractive solutions to the dermal aspect of this complex ageing process (Rohrich and Pessa, 2007; Mendelson and Wong, 2012). Initially, these agents will always cause a foreign body reaction when first injected into the host tissue (Strawford, 2020). Collagen stimulation results as part of the normal healing response of the body. After the inflammatory phase, initially producing type III collagen, microparticles of the filler become encapsulated as part of a natural protective mechanism (Strawford, 2020). This mechanism produces a stable capsule of mainly type I collagen and lasts as long as the biomaterial is present within the tissue (Strawford, 2020).
A systematic review of the literature by Fakhre et al (2009) reported patient satisfaction regarding cosmetic treatment experiences using Radiesse® through a meta-analysis. Results of past outcomes compared to their institutional study showed differences in results, and they concluded that, while it was a viable option for augmentation of facial soft tissue, accurate large scale population outcome assessments were mandatory (Fakre et al, 2009).
A 2016 systematic review reported by Shi et al (evidence level 2) evaluated complications relating to the injection of calcium hydroxylapatite (CaHA) for facial soft tissue augmentation (Shi et al, 2016). Only randomised controlled trials (RCTs) or controlled trials comparing CaHA injection of the nasolabial fold to either placebo or an active comparator for facial cosmetic use were included. Outcome measures were the count and frequency of complications, which were a range of different side effects. Subgroups evaluated were CaHA and lidocaine versus CaHA alone and CaHA versus hyaluronic acid (HA) filler. Findings supported the addition of lidocaine to nasolabial fold injection of CaHA, concluding that there was no significant effect on oedema, erythema, ecchymosis, pain or pruritus where lidocaine was added to CaHA for therapy. No significant difference was proven between CaHA versus HA for haematomas or nodules. There was no significant publication bias detected in either subgroups (Shi et al, 2016).
Methodology and literature searches
In both cases, the search methodology began with a strategy to identify any existing systematic reviews on either substance or brand (as reported above). Peer-reviewed available evidence found since the last systematic review in 2016 was gathered by searching the same databases (i.e. PubMED, EMBASE and Cochrane, with the addition of CINAHL). Study inclusion criteria were also repeated from previous sytematic reviews (i.e. only reporting on RCTs or where there were not any, controlled trials; only peer-reviewed published data; and only in-vivo studies relating to facial rejuvenation). Studies in-vitro, unpublished and/or relating to rejuvenation of any other part of the body were excluded. Some general articles found through the searches are considered in the discussion section.
Collagen stimulants for facial rejuvenation can be used for volume restoration and contouring through bio-stimulation of tissues
However, medical subject headings searches were not repeated, rather, title headings using the terms: ‘Radiesse®’, ‘calcium hydroxylapatite’, ‘systematic review’ and/or ‘meta-analysis’. PubMed returned four relevant results, and EMBASE and CINAHL each brought back one relevant result. After duplicates were removed and abstracts scanned for inclusion criteria, only two articles were relevant. When the title term ‘calcium hydroxylapatite’ was searched with the title search terms, ‘fillers’ and/or ‘dermal fillers’, PubMed returned a combined nine relevant results, with a further three from EMBASE and two from CINAHL. When duplicates were removed, 10 results were relevant to facial rejuvenation between the databases, but only one met inclusion criteria. No systematic reviews were found in the Cochrane Library, but 18 trial results were returned, of which, three results met inclusion criteria.
PubMed, EMBASE and CINAHL were explored using and combining the title search terms: ‘Ellanse’, ‘polycaprolactone’, ‘systematic review’ and/or ‘meta-analysis’. However, no systematic reviews were found that were relevant to facial aesthetics. When the title term ‘polycaprolactone’ was searched with the title search terms ‘fillers’ and/or ‘dermal fillers’, PubMed returned a combined 13 relevant articles, with a further eight from EMBASE and two from CINAHL. Once duplicates were removed, only one article was relevant to inclusion criteria. No systematic reviews were found in the Cochrane Library for polycaprolactone either, but 19 trials were discovered, of which, three results met inclusion criteria, and one of which was a duplicate of the aforementioned search.
Results
The results of the search can be seen in Table 1.
Table 1. Results of the literature search
| Author, date and country | Study | Key outcomes | Study weaknesses |
|---|---|---|---|
| Vallejo et al, 2018. Spain | Comparing efficacy and costs of four facial fillers: Sculptra® (poly-l-lactic acid), Radiesse® (calcium hydroxylapatite [CaHA]), Aquamid® (polyacrylamide) and autologous fat in HIV-associated lipodystrophy. Twenty-four-month study of 147 patients | Despite the nonsignificant differences observed in the number of sessions and volume, autologous fat showed significantly lower costs than all synthetic fillers (p < 0.05). Permanent fillers and autologous fat achieve the most consistent results over time, with lipofilling being the most cost-effective procedure |
|
| Bertucci et al, 2017. US | Randomised study | Merz Jawline Grading Score found appropriate tool sensitive to calcium hydroxylapatite treatment in concordance with aesthetic outcomes using Global Aesthetic Improvement Score (GAIS) and FACE-Q |
|
| Schacter et al, 2017. US | Multi-centre, randomised, double-blind split-face study to evaluate pain in nasolabial folds using new formulation of CaHA and 0.3% lidocaine in 102 participants | CaHA with integral lidocaine significantly reduces pain and is as effective as CaHA |
|
| Yutskovskaya et al, 2014. Russia | Randomised, split-face, histomorphological study. Radiesse (CaHA) versus VOLUMA (HA) | At 4 months, collagen type III was greater with CaHA versus HA (P=0.0052). By 9 months, type I staining was higher with CaHA versus HA (P=0.0135), whereas type III was lower with CaHA than HA (P=0.0019). Staining for elastin, Ki-67 and angiogenesis was greatest with CaHA at both timepoints |
|
| Jeong et al, 2019. South Korea | A randomised, patient/evaluator-blinded, split-face study to compare the efficacy and safety of PCL and polynucleotide fillers in the correction of crow's feet | No significant difference in Crow's Feet Grading Scale, GAIS or Ra value on either side treated; however results show efficacy and safety achieved |
|
| Galadari et al, 2015. UAE | Randomised, prospective, blinded, split-face, single-centre study comparing PCL to HA filler for nasolabial fold treatment in 45 patients | Used Wrinkle Severity Grading Score (WSRS) and GAIS to compare safety, efficacy and duration. PCL showed statistically significant improvements on both scales, suggesting that PCL-based dermal fillers last longer |
|
| Moers-Carpi and Sherwood, 2013. US | Prospective, 24-month RCT using two different formulas of PCL-based dermal fillers to treat nasolabial folds. (Ellansé-S and Ellansé-M) in 40 participants | Used WSRS and GAIS. Ellansé-M lasts longer. Both are safe and effective |
|
Discussion
Evidence comparing CaHA to polycaprolactone (PCL), poly-l-lactic acid (PLLA), Profhilo®, polymethyl-methacrylate (PMMA), lipofilling, platelet-rich plasma and stem cell therapies is lacking. Generally, the literature evaluated shows that there is a need for larger, multicentre RCTs with histological studies to confirm results relating to all areas of the face. Currently, CaHA treatment is consensus-led (Sundaram and Emer, 2013) and Ellansé® is a manufacturer-led protocol (Moers-Carpi and Sherwood, 2013). Evidence for PCL soft tissue facial fillers has not yet been presented in the style of a systematic review.
Conclusions
Studies continue to show that PCL and CaHA are safe and effective. CaHa with lidocaine is shown to be less painful than CaHA alone. Furthermore, studies prove that CaHA and PCL lasts longer than an equivalent HA filler (Yutskovskaya et al, 2014; Galadari et al, 2015), and in the long term, stimulates more type I collagen than HA fillers, compared with Aquamid® and lipofilling (Vallejo et al, 2018). However CaHa and PCL are irreversible compared to HA fillers, which could be viewed as a barrier to patient safety. Neither are appropriate for use in the lips (Sundaram and Emer, 2013). Only one study exists in the literature regarding dissolving Ellansé® with methotrexate (Philibert et al, 2020). Nevertheless, CaHA and HA fillers should be complementary to each other, rather than competitive (Sundaram and Emer, 2013). Lipofilling was shown to be more cost-effective than CaHA (Vallejo et al, 2018), though, again, this needs to be confirmed with larger scale studies.
Key points
- Not all skin fillers are the same, and it is important to understand the difference between the varieties and their effects on the skin
- Calcium hydroxylapatite spheres are composed of calcium and phosphate ions that occur naturally in human tissue and are bioresorbable
- Polycaprolactone is a bioresorbable soft medical material used in Ellanse fillers and other medical devices, such as biodegradable sutures and orthopaedic implants
- Studies have shown that calcium hydroxylapatite and polycaprolactone last longer than hyaluronic acid fillers and have an excellent safety profile with minimal side effects
- Calcium hydroxylapatite and polycaprolactone fillers cannot be dissolved with hyaluronidase like hyaluronic acid fillers. Neither are indicated for use in the lips.
CPD reflective questions
- What type of filler family do calcium hydroxylapatite and polycaprolactone fillers belong to?
- Explain the mechanisms by which these agents rejuvenate the skin?
- Name two differences between calcium hydroxylapatite fillers and hyaluronic acid fillers
- Name two differences between polycaprolactone fillers and hyaluronic acid fillers